Hyperuricemia drives the development of nonalcoholic fatty liver disease (NAFLD). Pharmacological inhibition of xanthine oxidase (XO), a rate-limiting enzyme for uric acid (UA) production, has been demonstrated to improve hepatic steatosis in diet-induced obese mice. However, it remains unclear whether inhibition of XO improves nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, in terms of both liver inflammation and fibrosis. Here, we investigated the effects of febuxostat and allopurinol, two XO inhibitors clinically used for gout, on a mouse model of NASH. Furthermore, we conducted a single-arm, open-label intervention study with febuxostat for NAFLD patients with hyperuricemia. Despite a similar hypouricemic effect of the XO inhibitors on blood UA level, febuxostat, but not allopurinol, significantly decreased hepatic XO activity and UA levels in the NASH model mice. These reductions in hepatic XO activity and UA levels were accompanied by attenuation of insulin resistance, lipid peroxidation, and classically activated M1-like macrophage accumulation in the liver. Furthermore, in NAFLD patients with hyperuricemia, treatment with febuxostat for 24 weeks decreased the serum UA level, accompanied by reductions in the serum levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase. XO may represent a promising therapeutic target in NAFLD/NASH, especially in patients with hyperuricemia. Nonalcoholic fatty liver disease (NAFLD), one of the most common liver diseases worldwide 1 , is strongly associated with insulin resistance and features of metabolic syndrome such as obesity, hyperlipidemia, and type 2 diabetes 1,2. NAFLD ranges from simple steatosis to more advanced nonalcoholic steatohepatitis (NASH) characterized by steatosis in combination with inflammation and fibrosis 3,4. Besides insulin resistance, increased inflammatory cytokines, reactive oxygen species (ROS), and subsequent lipid peroxidation are thought to drive the progression of NASH, leading to liver cirrhosis and hepatocellular carcinoma 3,5. Thus, in addition to conventional approaches based on of diet-and exercise-related adjunct therapies, an effective therapeutic approach is urgently needed for NASH. Besides metabolic syndrome-related conditions, hyperuricemia, characterized by high serum uric acid (UA) levels, has also been linked to NAFLD. Several epidemiological studies have demonstrated that patients with NAFLD have significantly higher serum UA levels relative to controls, and elevated serum UA levels are an independent risk factor for NAFLD 6-8. Notably, UA itself has been reported to promote de novo lipogenesis and induce insulin resistance, both in vivo and in vitro, through increased NADPH oxidase (NOX)-mediated ROS